Preparation of fingolimod and its salts

ABSTRACT

The present application provide processes for the preparation of fingolimod and its pharmaceutically acceptable salts, process for the purification of fingolimod hydrochloride and process for the preparation of amorphous fingolimod hydrochloride.

This application is a National Stage Application under 35 U.S.C. §371 ofPCT International Application No. PCT/IB2012/000922 filed Apr. 27, 2012,which claims the benefit of Indian provisional application Nos.1502/CHE/2011 filed on Apr. 29, 2011; 1597/CHE/2011 filed on May 9,2011; 2401/CHE/2011 filed on Jul. 13, 2011; 4524/CHE/2011 filed on Dec.22, 2011 and U.S. Provisional Application Nos. 61/497,228, filed Jun.15, 2011; 61/499,957, filed Jun. 22, 2011; 61/527,742, filed Aug. 26,2011 and 61/595,189, filed Feb. 6, 2012, all of which are herebyincorporated by reference in their entireties.

INTRODUCTION

Aspects of the present application provide processes for the preparationof fingolimod and its pharmaceutically acceptable salts, process for thepurification of fingolimod hydrochloride and process for the preparationof amorphous fingolimod hydrochloride.

The drug compound known as “fingolimod hydrochloride” has chemical names2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride; or2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol hydrochloride. It hasthe structure of formula (I).

Fingolimod hydrochloride is a sphingosine 1-phosphate receptor modulatorand is the active ingredient in a product sold by Novartis as GILENYA®in the form of hard gelatin capsules for oral use, for the treatment ofpatients with relapsing forms of multiple sclerosis.

U.S. Pat. No. 5,604,229, describes a process for the preparation offingolimod hydrochloride performed by a nine step sequence starting from2-(4-octanoyl phenyl)ethyl acetate and the crucial reaction stepincludes the condensation of 2-(4-octylphenyl)ethyl iodide withdiethylacetamidomalonate in the presence of sodium ethoxide base andethanol, and a subsequent reduction with lithium aluminium hydride toobtain 2-acetamido-2-[2-(4-octylphenyl)ethyl]1,3-propanediol, which isacylated in the presence of acetic anhydride and pyridine to give1,3-propanediyl-2-acetamido-2-[2-(4-octylphenyl)ethyl]ylidene diacetate,followed by hydrolysis using lithium hydroxide to obtain fingolimod.Further, it discloses the use of sodium hydroxide, sodium methoxide,potassium hydride, butyl lithium, triethylamine, diisopropylethylamine,and 1,8-diazabicyclo[5.4.0]undeca-7-ene as bases in the condensationstep.

U.S. Pat. No. 6,284,915 discloses a process for the preparation offingolimod hydrochloride which involves reacting4′(2-iodoethyl)octanophenone with diethyl acetamido malonate, in thepresence of sodium hydride, to give diethyl acetamide-2-(4-octanoylphenyl)ethyl malonate, which is further reacted with sodium borohydridein methanol, followed by acetylation using acetic anhydride andpyridine, to obtain1-(4-(3-acetamide-4-acetoxy-3-acetoxymethyl)butylphenyl)octyl acetate,which is hydrolyzed using 1N sodium hydroxide and methanol to givefingolimod.

U.S. Pat. No. 6,605,744 discloses a process for the preparation offingolimod hydrochloride which involves reacting diethylacetamido-2-[4-octylphenyl)-2-oxomethylmalonate with sodium borohydridein methanol followed by acetylation using acetic anhydride/pyridine togive 2-acetamido-4-acetoxy-2-acetoxymethyl-4-(4-octylphenyl)butylacetate which is hydrolyzed to obtain2-acetamido-2-[2-hydroxy-2-(4-octylphenyl)ethyl]propane-1,3-diol, whichis further subjected to reduction in the presence of 5% Pd/carbon inethanol, followed by treatment with 1N hydrochloric acid in ethanol togive fingolimod hydrochloride.

International Application Publication No. WO 20091115534 A1 disclosesprocesses for the preparation of intermediates useful in the preparationof fingolimod or its salts.

Chinese Patent Application Publication No. 1765872 discloses a processfor the preparation of fingolimod hydrochloride, which involves thereaction steps as depicted in Scheme 1 below.

Chinese Patent Application Publication Nos. 1528738, 1483721, and1814583, and Japanese Patent Publication No. 4079505 also disclosevarious processes for the preparation of fingolimod hydrochloride andrelated intermediates.

An article by B. Kalita et al., “Synthesis of 2-Nitroalcohols byRegioselective Ring Opening of Epoxides with MgSO₄/MeOH/NaNO₂System: AShort Synthesis of Immunosuppressive Agent FTY-720,” Synlett 2001, No.9, pages 1411-1414, discloses a process for the preparation offingolimod which involves the reaction steps depicted in Scheme 2 below.

International Application Publication No. WO 2010/055028 A2 disclosescrystalline forms of fingolimod hydrochloride salt which are designatedas Forms I, II, III, and IV. The publication also discloses acrystalline fingolimod hydrochloride salt, wherein the salt issubstantially in the form of a hydrate.

International Application Publication No. WO 2011/009634 A2 disclosespure polymorphic form B and a mixture of polymorphic forms A and B offingolimod hydrochloride, characterized by X-ray diffraction anddifferential scanning calorimetry. The publication also disclosesprocesses for the preparation of polymorphic forms, wherein one of theprocesses for the preparation of polymorphic form B involves dissolvingfingolimod hydrochloride in water and subjecting the solution tofreeze-drying.

Despite the existence of various processes for the preparation offingolimod or its salts, there remains a need for improved processes forthe preparation of fingolimod and its salts, producing high yields andpurity, and being well-suited for use on an industrial scale.

Further, there also remains a need for additional polymorphic forms offingolimod hydrochloride, and processes for making them.

SUMMARY

In an aspect, the present application provides a process for thepreparation of fingolimod or its salt, embodiments comprising:

a) reducing octanophenone of formula (II):

using a Lewis acid and a trialkyl silane to obtain octylbenzene offormula (III);

b) reacting the compound of formula (III) with a 3-halopropionyl halideto obtain a compound of formula (IV):

wherein X is a halogen;

c) reacting the compound of formula (IV) with a compound of formula (V):M^(+n)(NO₂)_(n)  (V)wherein M is a metal ion and n is 1, 2, or 3 to obtain a compound offormula (VI); and

d) converting the compound of formula (VI) to fingolimod of formula(Ia):

or its salt.

In an aspect, the present application provides a process for thepreparation of fingolimod or its salt comprising:

a) reducing 3-nitro-1-(4-octylphenyl)propan-1-one of formula (VI):

using a Lewis acid and a trialkyl silane to obtain a compound of formula(VII); and

b) converting the compound of formula (VII) to finaolimod of formula(Ia):

or its salt.

In an aspect, the present application provides processes for thepreparation of fingolimod or its salt, embodiments comprising:

a) reacting the compound of formula (IX),

with a reducing agent, to obtain the compound of formula (VII); and

b) converting the compound of formula (VII) to fingolimod or its salt.

In an aspect, the present application provides processes for thepreparation of fingolimod or its salt, embodiments comprising:

a) reacting the compound of formula (VII),

with paraformaldehyde, in the presence of a base, to obtain the compoundof formula (VIII); and

b) converting the compound of formula (VIII) to fingolimod or its salt.

In an aspect, the present application provides processes for thepreparation of fingolimod or its salt, embodiments comprising:

a) reacting a compound of formula (X),

wherein X is a leaving group, with a compound of formula (XI),

wherein R is a C₁-C₄ alkyl group, in the presence of a metal carbonate,to give a compound of formula (XII);

b) reacting the compound of formula (XII) with a reducing agent toprovide the compound of formula (XIII); and

c) converting the compound of formula (XIII) to fingolimod or its salt.

In an aspect the present application provides process for thepurification of fingolimod hydrochloride comprising:

(a) providing a solution of fingolimod hydrochloride in methanol ormethanol and ethylacetate mixture;

(b) optionally adding ethylacetate;

(c) cooling the solution to a temperature below 10° C.;

(d) isolating fingolimod hydrochloride.

In an aspect, the present application provides an amorphous fingolimodhydrochloride.

In an aspect, the present application provides processes for thepreparation of amorphous fingolimod hydrochloride, embodimentscomprising:

a) providing a solution of fingolimod hydrochloride and apharmaceutically acceptable carrier in a solvent; and

b) obtaining amorphous fingolimod hydrochloride.

In an aspect, the present application provides pharmaceuticalcompositions comprising amorphous fingolimod hydrochloride, togetherwith one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a powder X-ray diffraction (PXRD) patternof fingolimod freebase, prepared according to Example 10.

FIG. 2 is an illustration of a powder X-ray diffraction (PXRD) patternof amorphous fingolimod hydrochloride, prepared according to Example 11.

FIG. 3 is an illustration of a PXRD pattern of amorphous fingolimodhydrochloride, prepared according to Example 12.

FIG. 4 is an illustration of a PXRD pattern of amorphous fingolimodhydrochloride, prepared according to Example 13.

DETAILED DESCRIPTION

In an aspect, the present application provides a process for thepreparation of fingolimod or its salt, embodiments comprising:

a) reducing octanophenone of formula (II):

using a Lewis acid and a trialkyl silane to obtain octylbenzene offormula (III);

b) reacting the compound of formula (III) with a 3-halopropionyl halideto obtain a compound of formula (IV):

wherein X is a halogen;

b) reacting the compound of formula (IV) with a compound of formula (V):M^(+n)(NO₂)_(n)  (V)wherein M is a metal ion and n is 1, 2, or 3 to obtain a compound offormula (VI); and

d) converting the compound of formula (VI) to fingolimod of formula(Ia):

or its salt.

Step a) involves reducing octanophenone of formula (II) using a Lewisacid and a trialkyl silane to obtain octyl benzene of formula (III).

Lewis acids that may be used in the process of step a) may be selectedfrom TiCl₄, AlCl₃, BF₃, or the like. The trialkylsilanes that may beused in the process of step a) may be selected from triethylsilane,trimethylsilane, triisopropyl silane, or the like. The amount of Lewisacid that may be used ranges from about 0.5 to about 3.0 molarequivalents per mole of the compound of formula (II) and the amount oftrialkyl silane that may be used ranges from about 2.0 to about 3.0molar equivalents or more per mole of the compound of formula (II).

In an embodiment, the reaction of step a) may be carried out using TiCl₄and triethylsilane.

The process of step a) may be carried out in the presence a solventselected from a halogenated hydrocarbon solvent such as dichloromethane,1,2-dichloroethane, trichloroethylene, perchloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbontetrachloride, or the like; a hydrocarbon solvent such as hexane,heptane, cyclohexane or the like; or mixtures thereof. The reaction ofstep a) may be carried out at temperatures ranging from about −40° C. toabout 40° C. or more. In an embodiment, the reaction of step a) may becarried out at temperatures ranging from about −25° C. to about 25° C.In an embodiment, the reaction of step a) may be carried out attemperatures ranging from −10° C. to about 5° C.

After the completion of the reaction, the compound of formula (III) mayoptionally be isolated and purified or the reaction mass comprising thecompound of formula (III) may be taken forward for the next step of theprocess. In an embodiment, the reaction mass comprising the compound offormula (III) is filtered through a hyflo bed and the filtrate is takenforward for the next step of the process.

Step b) involves reacting the compound of formula (III) with a3-halopropionyl halide to obtain a compound of formula (IV).

The step of reacting the compound of formula (III) with 3-halopropionylhalide to obtain a compound of formula (IV) may be carried out in thepresence of a Lewis acid and an organic solvent. Lewis acids that may beused in the process of step b) may be selected from TiCl₄, AlCl₃, BF₃,or the like. X in the compound of formula (IV) may be a chloro, bromo,or iodo. In an embodiment, the 3-halopropionyl halide that may be usedin the process of step b) may be 3-chloropropionyl chloride. Organicsolvents that may be used in the process of step b) may be selected froma halogenated hydrocarbon solvent such as but not limited todichloromethane, 1,2-dichloroethane, trichloroethylene,perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane,chloroform, carbon tetrachloride, or the like. In an embodiment, thesolvent selected in step b) is the same solvent used in step a).

The reaction of step b) may be carried out at temperatures ranging fromabout −40° C. to about 40° C. or more. In an embodiment, the addition ofa Lewis acid and 2-halopropionyl halide to the reaction mass may becarried out at temperatures less than 10° C. and the reaction mass maybe maintained at a temperature ranging from about −10° C. to about 10°C. until the completion of the reaction.

After the completion of the reaction, the compound of formula (IV) mayoptionally be isolated by techniques known in the art and purified orthe reaction mass comprising the compound of formula (IV) may be takenforward for the next step of the process. In an embodiment, after thecompletion of the reaction, the reaction mass is added to waterprecooled to 5-10° C., organic layer is separated, washed with aqueoussodium bicarbonate solution and the resultant organic layer isoptionally dried and concentrated under reduced pressure to obtain acompound of formula (IV). Optionally, the compound of formula (IV) maybe further purified.

In an embodiment, the compound of formula (IV) may be purified using ahydrocarbon solvent such as hexane, heptane, cyclohexane or the like.

Step c) reacting the compound of formula (IV) with a compound of formula(V) to obtain a compound of formula (VI).

The compound of formula (V) M^(+n)(NO₂)_(n) that may be used in step c)may be selected from lithium nitrite, sodium nitrite, potassium nitrite,silver nitrite, or the like. Step c) may be carried out in the presenceof solvents that may be selected from but not limited todimethylformamide, diethylformamide, dimethyl sulfoxide,tetrahydrofuran, acetone, acetonitrile, methanol, methanol/water,isopropyl alcohol, ethyl acetate, or mixtures thereof. The process ofstep c) may be carried at temperatures ranging from about −80° C. toabout 80° C. or more based on the solvent employed. In an embodiment,step c) may be carried at temperatures ranging from about 25° C. toabout 50° C. In another embodiment, step c) may be carried attemperatures ranging from about 30° C. to about 35° C.

In an embodiment, the compound of formula (IV) is reacted with sodiumnitrite in the presence of ethyl acetate.

After the completion of the reaction, the compound of formula (VI) mayoptionally be isolated by techniques known in the art and optionallypurified. In an embodiment, after the completion of the reaction, thereaction mass is added to water, added ethyl acetate, organic layer isseparated, washed with aqueous sodium bicarbonate solution and/or brinesolution and the resultant organic layer is dried and concentrated underreduced pressure to obtain a compound of formula (VI). Optionally, thecompound of formula (VI) may be further purified from ethylacetate andn-hexane or by recrystallization using an alcohol selected frommethanol, ethanol, isopropanol or the like.

Step d) involves converting the compound of formula (VI) to fingolimodof formula (Ia) or its salts.

The compound of formula (VI) may be converted to fingolimod or its saltsby the processes known in the art for example CN1765872 or by theprocesses disclosed in the present application.

In an embodiment, the compound of formula (VI) is reacted with 10% Pd oncarbon under a hydrogen atmosphere in the presence of methanol at 25-30°C. and in further steps is converted to fingolimod. After completion ofreaction, fingolimod or its hydrochloride salt may be isolated accordingto known processes.

In an embodiment, the compound of formula (VI) is subjected to reductionusing a Lewis acid and a trialkyl silane to obtain a compound of formula(VII), which in further steps is converted to fingolimod or its saltsthereof.

In an aspect, the present application provides a process for thepreparation of fingolimod of formula (Ia)

or its salt comprising:

a) reducing 3-nitro-1-(4-octylphenyl)propan-1-one of formula (VI):

using a Lewis acid and a trialkyl silane to obtain a compound of formula(VII); and

b) converting the compound of formula (VII) to fingolimod of formula(Ia):

or its salt.

Step a) involves reducing the compound of formula (VI) using a Lewisacid and a trialkyl silane to obtain a compound of formula (VII). Lewisacids that may be used in the process of step a) may be selected fromTiCl₄, AlCl₃, BF₃, or the like. Trialkyl silanes that may be used in theprocess of step a) may be selected from triethylsilane, trimethylsilane,triisopropyl silane, or the like. The amount of Lewis acid that may beused ranges from about 0.5 to about 3.0 molar equivalents per mole ofthe compound of formula (VI) and the amount of trialkyl silane that maybe used ranges from about 2.0 to about 3.0 molar equivalents per mole ofthe compound of formula (VI).

The process of step a) may be carried out in the presence a solventselected from a halogenated hydrocarbon solvent such as dichloromethane,1,2-dichloroethane, trichloroethylene, perchloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbontetrachloride, or the like; a hydrocarbon solvent such as hexane,heptane, cyclohexane or the like; or mixtures thereof. The reaction ofstep a) may be carried out at temperatures ranging from about −40° C. toabout 40° C. or more. In an embodiment, the reaction of step a) may becarried out at temperatures ranging from about −25° C. to about 25° C.In an embodiment, the reaction of step a) may be carried out attemperatures ranging from about −10° C. to about 5° C. In an embodiment,the reaction of step a) may be carried out using TiCl₄ andtriethylsilane.

After the completion of the reaction, the compound of formula (VII) mayoptionally be isolated and purified or the reaction mass comprising thecompound of formula (VII) may be taken forward for the next step of theprocess. In an embodiment, the reaction mass comprising the compound offormula (VII) is filtered optionally through a hyflo bed to remove andthe filtrate is taken forward for the next step of the process. In anembodiment, after the completion of the reaction, water precooled to0-10° C. is added to reaction mass, organic layer is separated, washedwith aqueous sodium bicarbonate solution and the resultant organic layeris optionally dried and concentrated under reduced pressure to obtain acompound of formula (VII).

Step b) involves converting the compound of formula (VII) to fingolimodor its salt. The compound of formula (VII) may be converted tofingolimod or its salts by the processes known in the art or by theprocesses disclosed in the present application.

In an embodiment, the compound of formula (VII) may be converted tofingolimod or its salt by processes comprising:

(i) reacting the compound of formula (VII):

with paraformaldehyde to obtain a compound of formula (VIII); and

(ii) reacting the compound of formula (VIII) with a reducing agent toobtain fingolimod of formula (Ia):

or its salt.

The compound of formula (VII) may be reacted with paraformaldehyde, inthe presence of a base, to obtain the compound of formula (VIII).Suitable bases that may be used for this above step include, but are notlimited to, organic bases such as diethylamine, triethylamine,n-butylamine, propylamine, diisopropylethylamine, dicyclohexylamine, orthe like; inorganic bases such as sodium carbonate, potassium carbonateor the like. The process of step i) may be carried out in the presenceof solvent, including alcohols such as methanol, ethanol, or the like;polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide,tetrahydrofuran, acetone, acetonitrile, or the like; aromatic solventssuch as toluene, xylene or the like or mixtures thereof. The reactionmay be carried out at temperatures ranging from about 0° C. to about 65°C. or more based on the solvent employed.

Reducing agents that may be used in step ii) of this process include,but are not limited to: compounds such as sodium borohydride, lithiumborohydride, or lithium aluminium hydride; or Pd on carbon, Raney®nickel, or Pd(OH)₂, under a hydrogen atmosphere. The reduction processof step ii) may be carried out in the presence a solvent, including:alcohols such as methanol, ethanol, tert-butyl alcohol, or the like;tetrahydrofuran; diethyl ether; dioxane; acetone; ethyl acetate;toluene; etc. The reduction may be carried out at temperatures rangingfrom about 0° C. to about 45° C. or higher or about 25° C. to about 35°C., based on the reagents and solvents employed. In particularembodiment, the compound of formula (VIII) is reacted with 10% Pd oncarbon under a hydrogen atmosphere in the presence of methanol at 25-30°C., to give fingolimod. After completion of reaction, fingolimod or itssalts may be isolated according to known processes, or by processesdisclosed in the present application.

In an embodiment, the present application provides process for thepreparation of fingolimod of formula (Ia) or its salt comprising:

a) reducing 3-nitro-1-(4-octylphenyl)propan-1-one of formula (VI):

using a Lewis acid and a trialkyl silane to obtain a compound of formula(VII); and

b) reacting the compound of formula (VII):

with paraformaldehyde to obtain a compound of formula (VIII); and

c) reacting the compound of formula (VIII) with a reducing agent toobtain fingolimod of formula (Ia):

or its salt.

The above steps may be carried out according to the process described inthe present application.

In an embodiment, the present application provides process for thepreparation of fingolimod of formula (Ia):

or its salt comprising:

(a) reacting the compound of formula (VII):

with paraformaldehyde in the presence of potassium carbonate to obtain acompound of formula (VIII); and

(b) reacting the compound of formula (VIII) with a reducing agent toobtain fingolimod of formula (Ia) or its salt.

In an aspect, the present application provides a process comprisingreducing octanophenone of formula (II):

using a Lewis acid and a trialkyl silane to obtain octylbenzene offormula (III):

In an aspect, the present application provides the process furthercomprising reacting the compound of formula (III) with a 3-halopropionylhalide to obtain a compound of formula (IV):

wherein X is a halogen.

In an aspect, the present application provides the process furthercomprising reacting the compound of formula (IV) with a compound offormula (V):M^(+n)(NO₂)_(n)  (V)wherein M is a metal ion and n is 1, 2, or 3 to obtain a compound offormula (VI):

In an aspect, the present application provides a process comprisingreducing 3-nitro-1-(4-octylphenyl)propan-1-one of formula (VI):

using a Lewis acid and a trialkyl silane to obtain a compound of formula(VII):

In an aspect, the present application provides processes for thepreparation of fingolimod or its salt, embodiments comprising:

a) reacting the compound of formula (IX),

with a reducing agent, to obtain the compound of formula (VII); and

b) converting the compound of formula (VII) to fingolimod or its salt.

Step a) involves reacting the compound of formula (IX) with a reducingagent to obtain the compound of formula (VII).

The compound of formula (IX) may be obtained by any process, includingprocesses described in the literature. For example, the compound offormula (IX) may be prepared by the process described in Chinese PatentPublication 1765872, or by a process described in the presentapplication.

Reducing agents that may be used in step a) include, without limitationthereto, Pd on carbon, Raney nickel, and Pd(OH)₂, under a hydrogenatmosphere, or triethylsilane and trifluoroacetic acid.

In embodiments, triethylsilane and trifluoroacetic acid is used as thereducing agent.

Step b) involves converting the compound of formula (VII) to fingolimodor its salt.

The compound of formula (VII) may be converted to fingolimod or itssalts by a process described in the present application.

In embodiments, the compound of formula (VII) may be converted tofingolimod or its salt by processes comprising:

(i) reacting the compound of formula (VII),

with paraformaldehyde to obtain a compound of formula (VIII); and

(ii) reacting the compound of formula (VIII) with a reducing agent toobtain fingolimod or its salt.

The compound of formula (VII) can be reacted with paraformaldehyde, inthe presence of a base, to obtain the compound of formula (VIII).

Suitable bases that may be used for this above step include, but are notlimited to, organic bases such as diethylamine, triethylamine,n-butylamine, propylamine, disiopropylethylamine, dicyclohexylamine, andthe like.

The process of step i) may be carried out in the presence a solvent,including alcohols such as methanol, ethanol, and the like, and thereaction may be carried out at temperatures ranging from about 0° C. toabout 40° C., or about 25° C. to about 35° C.

Reducing agents that may be used in step ii) of this process include,but are not limited to: compounds such as sodium borohydride, lithiumborohydride, and lithium aluminium hydride; Pd on carbon, Raney nickel,and Pd(OH)₂, under a hydrogen atmosphere.

The reduction process of step ii) may be carried out in the presence asolvent, including: alcohols such as methanol, ethanol, tert-butylalcohol, and the like; tetrahydrofuran; diethyl ether; dioxane; acetone;ethyl acetate; toluene; etc. The reduction may be carried out attemperatures ranging from about 0° C. to about 45° C. or higher, orabout 25 to about 35° C., based on the reagents and solvents employed.

In particular embodiments, the compound of formula (VIII) are reactedwith 10% Pd on carbon under a hydrogen atmosphere in the presence ofethanol at 25-35° C., to give fingolimod. After completion of reaction,fingolimod or its salts may be isolated according to known processes, orby processes disclosed in the present application.

It has been found that repeating the process sequence involving thereactions of the compound of formula (IX) with paraformaldehyde andtriethylamine, followed by reduction of the hydroxyl function groupadjacent to the phenyl group, using the conditions disclosed in ChinesePatent Publication 1765872, does not result in the desired product.Further, it has been found that the step of reducing the hydroxylfunctional group adjacent to the phenyl group gives multiple spots by athin layer chromatography analysis, and may be the reason for the lowreported yield.

It was surprisingly found that altering the reaction sequence asdescribed herein provides higher yield and purity of the fingolimod.

In an aspect, the present application provides processes for thepreparation of fingolimod or salt thereof, embodiments comprising:

a) reacting the compound of formula (VII),

with paraformaldehyde in the presence of a base, to obtain the compoundof formula (VIII); and

b) converting the compound of formula (VIII) to fingolimod or its salt.

Step a) involves reacting a compound of formula (VII) withparaformaldehyde in the presence of a base, to obtain the compound offormula (VIII).

Suitable bases that may be used for this step include, but are notlimited to, organic bases such as diethylamine, triethylamine,n-butylamine, propylamine, disiopropylethylamine, dicyclohexylamine, andthe like.

The process of step a) may be carried out in the presence a solvent,including alcohols such as methanol, ethanol, and the like, and thereaction may be carried out at temperatures ranging from about 0° C. toabout 40° C., or about 25 to about 35° C.

It has been found that the above step as per the processes described inthe literature using Amberlyst A-21 resulted in product with highcontent of the starting material.

It has been found that the rate of reaction completion is accelerated inthe presence of a base, and the product is obtained with high yields andpurity.

Step b) converting the compound of formula (VIII) to fingolimod or itssalt.

The step of converting the compound of formula (VIII) to fingolimod orits salts may be carried out by using reducing agents.

Reducing agents that may be used in step b) include, but are not limitedto: compounds such as sodium borohydride, lithium borohydride, andlithium aluminium hydride; metals such as palladium on carbon, platinumoxide, and Raney nickel, Pd(OH)₂ under a hydrogen atmosphere.

The reduction process of step b) may be carried out in the presence asolvent, including, but not limited to: alcohols such as methanol,ethanol, tert-butyl alcohol, and the like; tetrahydrofuran; diethylether; dioxane; acetone; ethyl acetate; toluene; etc. The reduction maybe carried out at temperatures ranging from about 0° C. to about 45° C.or higher, or about 25 to about 35° C., based on the reagents andsolvents employed.

In particular embodiments, the compound of formula (VIII) are reactedwith 10% Pd on carbon under a hydrogen atmosphere in the presence ofethanol at 25-35° C., to give fingolimod. After completion of reaction,fingolimod or its salts may be obtained according to known processes, orby processes disclosed in the present application.

In an embodiment, fingolimod hydrochloride may be obtained by dissolvingfingolimod of step b) in ethanol, cooling the reaction mixture to 0° C.to 5° C., adding ethanolic hydrochloride solution drop wise over aperiod of 10 to 30 minutes at the same temperature to obtain asuspension, maintaining the suspension at the same temperature for 1 to3 hours, filtering the obtain solid, washing with an ether solvent andoptionally drying the product obtained to give fingolimod hydrochloride.

In an aspect, the present application provides processes for thepreparation of fingolimod or its salt thereof, embodiments comprising:

a) reacting the compound of formula (IX),

with a reducing agent to obtain the compound of formula (VII);

b) reacting the compound of formula (VII) with paraformaldehyde toobtain the compound of formula (VIII); and

c) converting the compound of formula (VIII) to fingolimod or its salt.

In an aspect, the present application provides processes for thepreparation of fingolimod or its salt, embodiments comprising:

a) reacting a compound of formula (X),

wherein X is a leaving group, with a compound of formula (XI),

wherein R is a C₁-C₄ alkyl group, in the presence of a metal carbonate,to give a compound of formula (XII);

b) reacting the compound of formula (XII) with a reducing agent toprovide the compound of formula (XIII); and

c) converting the compound of formula (XIII) to fingolimod or its salt.

Step a) involves reacting a compound of formula (X) with a compound offormula (XI) in the presence of a metal carbonate, to give a compound offormula (XII).

The compound of formula (X) may be obtained using any process, includingprocesses described in the literature. For example, the compound offormula (X) may be prepared by a process described in U.S. Pat. No.5,604,229 or by a process described in the present application.

Leaving groups that may be used in the process of step a) may be halogengroups, such as chloro, bromo, iodo, and the like.

C₁-C₄ alkyl groups for the compound of formula (XI) may be, for example,methyl, ethyl, isopropyl, and the like.

Metal carbonates that may be used in the step include sodium carbonate,potassium carbonate, cesium carbonate, and the like.

Typical amounts of metal carbonate used in step a) range from about 1 toabout 4 molar equivalents, per molar equivalent of the compound offormula (X).

It has been found that the use of sodium methoxide or sodium ethoxide inthe above step, as in processes described in the literature, result inlow yields and a product having high concentrations of impurities, forexample the undesired compound of formula (A).

This finding is supported by N. Matsumoto et al., “Synthesis of the KeyIntermediate, Diethyl2-Acetylamino-2-(2-(4-octanoylphenyl)ethyl)propane-1,3-dioate, of theImmunomodulatory Agent FTY720 (Fingolamod),” Chemical & PharmaceuticalBulletin, Vol. 56(4), pages 595-597, 2008 wherein the compound offormula (A) is prepared by reacting the compound of formula (X) (where Xis Br) with sodium ethoxide, in the presence of ethanol and at atemperature of 60° C., for 1 hour.

It has been found that the rate of reaction completion is accelerated inthe presence of metal carbonates, and the product is obtained with highyields and purity, e.g., with a content of the impurity compound offormula (A) less than about 10%, or less than about 5%, or less thanabout 1%, or less than about 0.5%.

The reaction of step a) may be carried out in the presence of a solvent.Useful solvents include, without limitation thereto, polar aproticsolvents such as dimethylsulphoxide, N,N-dimethylformamide,N-methylpyrrolidone, tetrahydrofuran, acetonitrile, and the like.

The reaction may be carried out at temperatures ranging from about 25°C. to about 100° C., or about 60° C. to about 90° C.

After the completion of the reaction, the compound of formula (XII) maybe isolated and optionally purified.

In a particular embodiment, the compound of formula (X) is reacted withthe compound of formula (XI) in the presence of cesium carbonate anddimethylsulfoxide, to give a compound of formula (XII).

Step b) involves reacting the compound of formula (XII) with a reducingagent, to provide a compound of formula (XIII).

Reducing agents that may be used include, but are not limited to, sodiumborohydride, lithium aluminium hydride, and the like.

The amounts of reducing agents that may be used range from about 1 toabout 8 molar equivalents, per molar equivalent of the compound offormula (XII).

The process of step b) may be carried out in the presence a solvent, forexample the alcohols methanol, ethanol, and the like, and the reactionmay be carried out at temperatures ranging from about 0° C. to about 40°C., or about 25° C. to about 35° C.

In a particular embodiment, the compound of formula (XII) is reactedwith sodium borohydride, in the presence of methanol, to give a compoundof formula (XIII).

After completion of the reaction, the compound of formula (XIII) may beisolated and optionally purified. In embodiments, after completion ofthe reaction, the reaction mixture is optionally concentrated to form asolid, dissolved in water, and extracted with an organic solvent, suchas ethyl acetate. The organic extract is washed with water and thenbrine solution, and concentrated under reduced pressure to give thecompound of formula (XIII). The product obtained can be further purifiedby column chromatography, such as using 100-200 mesh silica gel andethyl acetate-hexane as the eluent system.

Step c) converting the compound of formula (XIII) to fingolimod or itssalts

The step of converting the compound of formula (XIII) to fingolimod orits salts may be carried out by hydrolysis using an acid or a base.

The acids that may be used include mineral acids such as aqueoushydrochloric acid, aqueous sulphuric acid, aqueous phosphoric acid,aqueous perchloric acid, aqueous hydrobromic acid, or carrierscontaining an acid such as acidic resins. The bases that may be usedinclude, but are not limited to, aqueous methylamine, aqueous ammonia,and iodine in methanol.

In a particular embodiment, an acid that may be used in the above stepincludes aqueous hydrochloric acid having concentrations about 0.5N toabout 5N.

The reaction may be carried out at temperatures ranging from about 0° C.to about reflux temperatures. After completion of reaction, fingolimodor its salts may be isolated according to known processes, or byprocesses disclosed in the present application.

In an aspect, the present application provides processes for thepreparation of fingolimod hydrochloride, embodiments comprising;

a) reacting the compound of formula (Xa),

with the compound of formula (XIa),

in the presence of a metal carbonate, to give the compound of formula(XIIa);

b) reacting the compound of formula (XIIa) with a reducing agent toprovide the compound of formula (XIII); and

c) converting the compound of formula (XIII) to fingolimod or itshydrochloride its salts.

In an aspect the present application provides process for thepurification of fingolimod hydrochloride comprising:

(a) providing a solution of fingolimod hydrochloride in methanol ormethanol and ethylacetate mixture;

(b) optionally adding ethylacetate;

(c) cooling the solution to a temperature below 10° C.;

(d) isolating fingolimod hydrochloride.

Providing a solution in step a) includes obtaining a solution offingolimod hydrochloride in methanol or methanol and ethylacetatemixture as a final step in the preparation of the compound or dissolvingfingolimod hydrochloride in methanol or dissolving fingolimodhydrochloride in methanol and adding ethyl acetate or vice-versa ordissolving fingolimod hydrochloride in methanol and ethylacetatemixture.

The solution in step a) may be provided at any temperature ranging fromabout 0° C. to about bailing point of the solvent, and preferably attemperatures about 20° C. to about 35° C., more preferably attemperatures about 25° C. to about 30° C.

The solution may optionally be treated with activated charcoal and thenfiltered to remove the carbon.

The solution may optionally be filtered by passing through paper, glassfiber, or other membrane material, or a bed of a clarifying agent suchas Celite. Depending upon the equipment used, as well as theconcentration and temperature of the solution, the filtration apparatusmay need to be heated or cooled to avoid undesired crystallization.

Optionally, ethylacetate may be added to the solution obtained in stepa). In an embodiment, ethylacetate is added to the solution obtained instep a) and taken forward for the next step.

The solution obtained in step a) or step b) may be cooled to atemperature below 10° C. to precipitate the solid. In embodiments, thesolution may be cooled to temperatures about 0° C. to about 5° C.

The solid obtained from step c) may be collected using known techniques.

Drying may be suitably carried out using any of equipment at atmosphericpressure or under reduced pressures, at temperatures less than about 40°C., less than about 30° C., less than about 20° C. and any othersuitable temperatures. The drying may be carried out for any timeperiods required for obtaining a desired quality, such as from about 15minutes to several hours, or longer.

In an aspect, the present application provides amorphous fingolimodhydrochloride.

In an aspect, the present application provides processes for thepreparation of amorphous fingolimod hydrochloride, embodimentscomprising:

a) providing a solution of fingolimod hydrochloride and apharmaceutically acceptable carrier in a solvent; and

b) obtaining amorphous fingolimod hydrochloride.

Step a) involves providing a solution of fingolimod hydrochloride and apharmaceutically acceptable carrier in a solvent.

Providing a solution in step a) includes obtaining a solution offingolimod hydrochloride in a solvent, as a final step in thepreparation of the compound, and dissolving a pharmaceuticallyacceptable carrier in the solution, or dissolving fingolimodhydrochloride in a suitable solvent, along with a pharmaceuticallyacceptable carrier. Alternatively, a solution containing the fingolimidhydrochloride and a separate solution containing a pharmaceuticallyacceptable carrier can be combined.

Any polymorphic form of fingolimod hydrochloride may be utilized forproviding the solution of fingolimod hydrochloride in step a).

Fingolimod hydrochloride that may be used as the input for a process ofthe present application may be obtained by any process, including theprocesses described in the literature. For example, fingolimodhydrochloride may be prepared by the processes described in U.S. Pat.No. 5,604,229.

Suitable solvents that may be used in step a) include, but are notlimited to, water, alcohols such as methanol, ethanol, n-propanol,n-butanol, and any mixtures of two or more thereof.

Pharmaceutically acceptable carriers that may be used in this stepinclude a polyvinylpyrrolidone (povidone or PVP), a hydroxypropylcellulose (HPC), a hydroxypropyl methylcellulose (hypromellose or HPMC),a hydroxyethyl cellulose (HEC), and the like. Any mixtures of two ormore thereof also will be useful. In specific embodiments, apharmaceutically acceptable carrier is a povidone K-30 grade.

The dissolution temperatures may range from about −20° C. to about thereflux temperature of the solvent, depending on the solvent used fordissolution, as long as a clear solution of fingolimod hydrochloride isobtained without affecting its quality. Optionally, the solution may befiltered to remove any insoluble particles. The insoluble particles maybe removed suitably by filtration, centrifugation, decantation, and anyother suitable techniques. The solution may be filtered by passingthrough cloth, paper, glass fiber, or other membrane material. Dependingupon the equipment used and the concentration and temperature of thesolution, the filtration apparatus may need to be preheated to maintainthe solution

Step b) involves obtaining an amorphous fingolimod hydrochloride fromthe solution of step a).

In embodiments, the product may be obtained by removing solvent.Suitable techniques that may be used for the removal of solvent include,but are not limited to, using a rotational distillation device such as aBüchi® Rotavapor®, spray drying, thin-film drying, freeze-drying(lyophilization), etc.

The solvent may be removed, optionally under reduced pressures, attemperatures less than about 150° C., less than about 100° C., less thanabout 40° C., less than about 20° C., less than about 0° C., less thanabout −20° C., less than about −40° C., less than about −60° C., lessthan about −80° C., and any other suitable temperatures.

Freeze drying (lyophilization) may be carried out by freezing a solutionof fingolimod hydrochloride at low temperatures and reducing thepressure as required removing the solvent from the frozen solution offingolimod hydrochloride. Temperatures that may be required to freezethe solution, depend on the solvent chosen to make the solution offingolimod hydrochloride, may range from about −60° C. to about 0° C.,or up to about 45° C. Temperatures that may be required to remove thesolvent from the frozen solution may be less than about 45° C., lessthan about 0° C., less than about −20° C., less than about −40° C., lessthan about −60° C., and any other suitable temperatures.

Spray drying may be carried out by evaporating a solution of fingolimodhydrochloride at temperatures up to the boiling point of the solvent.

The solid obtained from step b) may be collected using techniques suchas scraping, shaking the container, or other techniques specific to theequipment used. The product thus obtained may optionally be furtherdried to improve its purity.

Drying may be suitably carried out using any of equipment such as agravity oven, spray dryer, tray dryer, vacuum oven, Büchi® Rotavapor®,air oven, fluidized bed dryer, spin flash dryer, flash dryer, and thelike. The drying may be carried out at atmospheric pressure or underreduced pressures, at temperatures less than about 80° C., less thanabout 60° C., less than about 40° C., less than about 20° C., less thanabout 0° C., and any other suitable temperatures. The drying may becarried out for any time periods required for obtaining a desiredquality, such as from about 15 minutes to several hours, or longer.

The dried product may optionally be milled to obtain desired particlesizes. Milling or micronization may be performed before drying, or afterthe completion of drying of the product. Techniques that may be used forparticle size reduction include, without limitation, ball, roller, andhammer mills, and jet mills.

In an aspect, the present application provides an amorphous fingolimodhydrochloride, characterized by a PXRD pattern substantially asillustrated by any one or more of FIG. 2, FIG. 3, and FIG. 4.

All PXRD data reported herein are obtained using a Bruker AXS D8 AdvancePowder X-ray Diffractometer, or a PANalytical X-ray Diffractometer, withcopper Kα radiation.

In an aspect, the present application provides pharmaceuticalcompositions comprising amorphous fingolimod hydrochloride, togetherwith one or more pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients include, but are not limited to,suitable surface modifiers. Such excipients include various polymers,low molecular weight oligomers, natural products, and surfactants.

In an embodiment, the processes of the present application providesfingolimod hydrochloride having a purity greater than about 99.9% asdetermined using HPLC.

In another aspect, the present application provides fingolimodhydrochloride having purity greater than about 99.9% and less than about0.1% of Impurity D and less than 0.1% of Impurity E as determined usingHPLC.

In another aspect, the present application provides fingolimodhydrochloride having purity greater than about 99.9% and less than about0.1% of Impurity F and less than 0.1% of Impurity Gas determined usingHPLC.

In yet another aspect, the present application provides fingolimodhydrochloride having purity greater than about 99.8% and with less thanabout 0.1% of each of the compound given in the table below:

Code Structure Impurity A

Impurity B

Impurity C

Impurity D

Impurity E

Impurity F

Impurity G

Impurity H

Impurity I

The purity of fingolimod hydrochloride and its related substances orimpurities may be analyzed using various methods. A representativeuseful HPLC method is described below.

Column: X Bridge C18, 150×4.6 mm, 3.5 μm

Column temperature: 60±2° C.

Injection volume: 10 μl

Diluent: Water:Acetonitrile (70:30)

Run time: 70 min

Mobile Phase A: Add 1.0 g of Tetrabutyl ammonium hydrogen sulphate(TBAHS) and 0.2 ml of ortho phosphoric acid to 1000 ml water, dissolveby sonication, filter and degass

Mobile Phase B: Mix Acetonitrile and water in the ratio of 9:1, filterand degass.

Flow rate: 1.0 ml/min

Wavelength of detection: 218 nm

Program: Gradient

Gradient program:

Time (min) % A % B 0 70 30 30 50 50 35 20 80 40 20 80 45 0 100 50 0 10050.1 70 30 70 70 30

In an aspect, the present application provides a crystalline fingolimodfreebase, characterized by a PXRD pattern substantially as illustratedby FIG. 1.

The crystalline fingolimod freebase may be prepared by a procedure asdepicted in Example 10 of the present application.

The X-ray powder diffraction patterns described herein were generatedusing a Bruker AXS D8 Advance powder X-ray diffractometer, with a copperK_(α) radiation source (1.5418 Å). Generally, a diffraction angle (20)in powder X-ray diffractometry may have a permissible variation in therange of ±0.2°. Therefore, the aforementioned diffraction angle valuesshould be understood as including values in the range of about ±0.2°.Accordingly, the present disclosure includes not only crystals whosepeak diffraction angles in powder X-ray diffractometry completelycoincide with each other, but also crystals whose peak diffractionangles coincide with each other with a permissible variation of about±0.2°. Although the intensities of peaks in the x-ray powder diffractionpatterns of different batches of a compound may vary slightly, the peaksand the peak locations are characteristic for a specific polymorphicform. The relative intensities of the PXRD peaks can vary depending onthe sample preparation technique, crystal size distribution, variousfilters used, the sample mounting procedure, and the particularinstrument employed. Moreover, instrument variation and other factorscan affect the 2-theta values.

Certain specific aspects and embodiments of the present application willbe explained in detail with reference to the following examples, whichare provided only for purposes of illustration and should not beconstrued as limiting the scope of the application in any manner.

EXAMPLES Example 1 Preparation of 3-chloro-1-(4-octylphenyl)propan-1-one

Octanophenone (50 g), dichloromethane (250 mL), and triethylsilane(69.77 g) are charged into a round bottom flask, stirred, and cooled to0-10° C. Titanium tetrachloride (55.7 g) in dichloromethane (250 mL) isadded to the reaction mixture over 30-35 minutes at temperature below10° C. and the reaction mixture is stirred at a temperature of 25-30° C.for about 1 hour. The reaction mixture is filtered through a hyflo bedand washed with dichloromethane (100 mL). The filtrate obtained ischarged into a second round bottom flask, aluminium chloride (41.6 g) isadded, and the reaction mixture is cooled to 0-5° C. 3-Chloropropionylchloride (30.47 g) in dichloromethane (50 mL) is added slowly to thereaction mixture at temperature below 5° C. and the reaction mixture isallowed to a temperature of 25-30° C. and maintained at the sametemperature for about 1 hour. The reaction mixture is slowly added towater (500 mL) precooled to 0° C. and stirred. The organic layer isseparated, washed with aqueous sodium bicarbonate solution (2×500 mL),water (500 mL), followed by brine solution (100 mL), dried over sodiumsulphate and concentrated under reduced pressure at a temperature ofabout 45° C. to obtain 3-chloro-1-(4-octylphenyl)propan-1-one.

Example 2 Preparation of 3-nitro-1-(4-octylphenyl)propan-1-one (FormulaVI)

3-Chloro-1-(4-octylphenyl)propan-1-one obtained in Example 1 anddimethylformamide (250 mL) are charged into a round bottom flask andstirred for dissolution at 25-30° C. Sodium nitrite (25.66 g) is chargedinto the flask and the reaction mixture is stirred 25-30° C. for about90 minutes. The reaction mixture is added to a mixture of water (500 mL)precooled to 0-5° C. and ethyl acetate (250 mL), stirred, and theorganic layer is separated. The aqueous layer is extracted with ethylacetate (250 mL) and the organic layer is combined with the initialorganic layer. The combined organic layer is washed with water (250 mL)followed by brine solution (100 mL), dried over sodium sulphate (50 g),and evaporated under reduced pressure at 45° C. to obtain the crudecompound. The crude compound is dissolved in hexane (500 mL) at 26° C.,is cooled to −10° C., and stirred for about 40 minutes at the sametemperature. The obtained solid is filtered, washed with precooledhexane (100 mL), and dried at 26° C. to give 37.0 g of the titlecompound.

Example 3 Preparation of 1-(3-nitropropyl)-4-octylbenzene (Formula VII)

3-Nitro-1-(4-octylphenyl)propan-1-one (37 g) and dichloromethane (185mL) are charged into a round bottom flask at 25-30° C. and stirred.Triethylsilane (36.87 g) is charged into the flask and the reactionmixture is cooled to 0-5° C. Titanium tetrachloride (28.9 g) indichloromethane (185 mL) is added to the reaction mixture over theperiod of 30 minutes at temperature below 5° C. and the reactionmixtures is stirred at a temperature of 25-30° C. for about 1 hour. Thereaction mixture is added to water (370 mL) precooled to 0-5° C.,stirred, and the organic layer is separated. The organic layer is washedwith aq. sodium bicarbonate (2×370 mL), followed by water (370 mL), andbrine solution (370 mL). The organic layer is dried over sodium sulphateand evaporated under reduced pressure at about 45° C. to give 64.0 g ofthe title compound.

Example 4 Preparation of 2-nitro-2-(4-octylphenethyl)propane-1,3-diol(Formula VIII)

1-(3-Nitropropyl)-4-octylbenzene (37 g) and methanol (190 mL) arecharged into a round bottom flask and stirred at 25-30° C.Paraformaldehyde (37 g) and triethylamine (38.52 g) are charged into theflask and the reaction mixture is heated to a reflux temperature (about68° C.). The reaction mixture is maintained at the same temperature forabout 2 hours and is cooled to a temperature of 25-30° C. The reactionmixture is evaporated under reduced pressure at a temperature of about45° C. to obtain crude compound. Water (190 mL) and ethyl acetate (190mL) are charged to the crude compound, stirred, and the organic layer isseparated. The aqueous layer is extracted with ethyl acetate (190 mL)and the organic layer is combined with the initial organic layer. Thecombined organic layer is washed with water (190 mL) followed by brinesolution (190 mL), dried over sodium sulphate, and evaporated underreduced pressure. Hexane (370 mL) is charged at 28° C. and the reactionmass is stirred at the same temperature for about 1 hour. The solidobtained is collected by filtration, washed with hexane (37 mL), anddried at 28° C. for about 3 hours to give 20.5 g of the title compound.

Example 5 Preparation of 2-amino-2-(4-octylphenethyl)propane-1,3-diolhydrochloride (Formula I)

2-Nitro-2-(4-octylphenethyl)propane-1,3-diol (5 g) and methanol (100 mL)are charged into a hydrogenation vessel and stirred at 25-30° C. 10%Pd/C (50% wet, 1 g) is charged into the vessel, a hydrogen pressure of 5Kg/cm² applied, and the reaction mixture is stirred at 25-30° C. forabout 4 hours. The reaction mixture is filtered through a hyflow bed andwashed with methanol (10 mL). The filtrate is charged into a roundbottom flask and ether hydrochloric acid (25 mL) is added to adjust thepH of the reaction mixture to 3. The reaction mixture is evaporatedunder reduced pressure at about 45° C. to obtain 15-20 mL of theconcentrated mass. The reaction mass is cooled to 0° C. and ethylacetate (50 mL) is added over a period of 15 minutes. The reactionmixture is maintained at 0-5° C. for about 1 hour and filtered. Thecollected solid is washed with precooled ethyl acetate (10 mL) and driedat about 26° C. for 3 hours to give 2.8 g of the title compound.

Example 6 Preparation of 3-nitro-1-(4-octylphenyl)propan-1-one (FormulaVI)

Octanophenone (250 g) and dichloromethane (1250 mL) are charged into around bottom flask at 25-30° C. and stirred. The mixture is cooled to−10° C. to −5° C. and triethylsilane (327.9 g) is added. A solution oftitanium tetrachloride (244.1 g) in dichloromethane (1250 mL) is addedover a period of 15 minutes and the obtained reaction mixture ismaintained at 0-5° C. for 3 hours. The reaction mixture is filteredthrough a hyflo bed, washed with dichloromethane (500 mL) and thefiltrate obtained is charged into a second round bottom flask. Thereaction mass (filtrate) is cooled to −10° C. to −5° C. and aluminiumchloride (213.2 g) is slowly added to the reaction mass over a period of15 minutes. A solution of 3-chloropropionyl chloride (173.5 g) indichloromethane (500 mL) is added over a period of 15 minutes and theobtained reaction mixture is maintained at −10° C. to −5° C. for 3hours. Water (2500 mL) precooled to 0-10° C. is slowly added at the sametemperature and the reaction mixture is stirred for about 1 hour at atemperature of 25-30° C. The organic layer is separated, washed with 5%sodium bicarbonate solution (1250 mL), followed by 20% brine solution(1250 mL) and the organic layer is concentrated under vacuum at 45° C.to obtain crude product (751 g). The crude product obtained and dimethylformamide (1500 mL) are charged into a round bottom flask at 25-35° C.and stirred. Sodium nitrite (135.5 g) is added and reaction mixture ismaintained at 30-35° C. for 3 hour. Water (2500 mL) and ethyl acetate(2500 mL) are added to the reaction mixture, stirred for 30 minutes. Theorganic layer is separated and the aqueous layer is extracted with ethylacetate (500 mL). The organic layers are combined, washed with 5% brinesolution (2×2500 mL) and concentrated under reduced pressure at 45° C.Hexane (500 mL) is added to the obtained compound and evaporated underreduced pressure at 45° C. to give the title compound.

Yield: 502 g

Purity by HPLC: 94.26%

Example 7 Purification of 3-nitro-1-(4-octylphenyl)propan-1-one (FormulaVI)

3-nitro-1-(4-octylphenyl) propan-1-one crude (16.5 g, Purity: 94.26%)and n-hexane (32 mL) are charged into a round bottom flask at 25-30° C.The reaction mixture is cooled to −15 to −10° C., maintained at the sametemperature for about 60 minutes and filtered. The obtained wet compoundand methanol (48 mL) are charged into a round bottom flask at 25-30° C.and stirred to obtain a clear solution. The solution is cooled to −15 to−10° C. and maintained at the same temperature for about 60 minutes. Theobtained solid is filtered, washed with methanol (8 mL) precooled to −5°C. to 0° C. and dried under vacuum at 35-40° C. to give the titlecompound.

Yield: 8.8 g

Purity by HPLC: 99.5%

Example 8 Preparation of 2-nitro-2-(4-octylphenethyl)propane-1,3-diol(Formula VIII)

3-nitro-1-(4-octylphenyl)propan-1-one (20 g) and dichloromethane (100mL) are charged into a round bottom flask at 25-30° C. and stirred. Themixture is cooled to −10° C. to 0° C. and triethylsilane (19.9 g) isadded. A solution of titanium tetrachloride (19.57 g) in dichloromethane(100 mL) is added over a period of 15 minutes and the obtained reactionmixture is maintained at −10 to 0° C. for 5 hours. Water (200 mL)precooled to 0-10° C. is slowly added to the reaction mixture over aperiod of 20 minutes and the temperature is allowed to raise to 25-30°C. The reaction mixture is stirred for about 1 hour, organic layer isseparated, washed with 5% sodium bicarbonate solution (100 mL), followedby 20% brine solution (100 mL), the organic layer is concentrated undervacuum at 45° C. to obtain 38.2 g of crude1-(3-nitropropyl)-4-octylbenzene. Toluene (200 mL) and crude1-(3-nitropropyl)-4-octylbenzene (38.2 g) are charged into the roundbottom flask at 25-30° C. and stirred. Potassium carbonate (18.96 g) andparaformaldehyde (7.21 g) are charged and the reaction mixture isstirred at the same temperature for about 6 hours. The reaction mixtureis filtered and washed with toluene (40 mL). The obtained filtrate,water (200 mL) and ethyl acetate (60 mL) are charged into a round bottomflask and stirred for 2 hours. The organic layer is separated, washedwith 5% hydrochloric acid solution (100 mL), 5% sodium bicarbonatesolution (100 mL) and followed by 5% brine solution (100 mL). Theresultant organic layer is concentrated under vacuum at below 45° C.n-Hexane (100 mL) is added to the obtained compound and stirred. Theobtained mixture is cooled to 0 to 5° C., maintained at the sametemperature for about 60 minutes, filtered and washed with n-hexane (20mL). The obtained wet compound and toluene (80 mL) are charged into around bottom flask, heated to 40-45° C. and maintained at the sametemperature for about 15 minutes. The reaction mixture is cooled to 0-5°C., maintained for about 45 minutes, filtered and washed the productwith toluene (40 mL) precooled to 0-5° C. and the product obtained isdried under vacuum at 25-30° C. to give the title compound.

Yield: 19 g

Purity by HPLC: 99.74%,

Impurity 1: <0.1%

Impurity 2: <0.1%

Impurity 3: <0.1%

Impurity 4: <0.1%

Example 9 Preparation of 2-amino-2-(4-octylphenethyl)propane-1,3-diolhydrochloride (Formula I)

2-nitro-2-(4-octylphenethyl)propane-1,3-diol (40 g) and methanol (600mL) are charged into a hydrogenation vessel at 25 to 30° C. and stirred.10% Pd/C (14 g) is charged into the vessel, a hydrogen pressure of 4-5Kg/cm² applied and the reaction mixture is maintained under the sameconditions for about 6 hours. The reaction mixture is filtered through ahyflo bed and washed with methanol (80 mL). The obtained filtrate ischarged into a round bottom flask, methanolic hydrochloric acid (47.3mL) is added and the reaction mass is stirred at 25-30° C. for 10minutes. The reaction mass is concentrated under reduced pressure at atemperature below 45° C. to obtain 104 mL of the concentrated solution.Ethyl acetate (600 mL) is added to the above concentrated solution,cooled to −5 to 0° C. and maintained at the same temperature for about 1hour. The solid obtained is filtered, washed with ethyl acetate (80 mL)precooled to 0-5° C. and suction dried. The wet compound and methanol(80 mL) are charged into a round bottom flask at 25-30° C. and stirredto obtain clear solution. Ethyl acetate (80 mL) is added to the abovesolution, stirred for 10 minutes and filtered through hyflo bed toremove undissovled particles. The bed is washed with mixture of methanol(40 mL) and ethyl acetate (80 mL). The obtained filtrate andethylacetate (440 mL) are charged into a round bottom flask, cooled to0-5° C. and maintained at the same temperature for about 60 minutes. Thesolid obtained is filtered, washed with ethylacetate (80 mL) and driedunder vacuum at 25-30° C. to give crystalline compound.

Yield: 26.0 g

Purity by HPLC: 99.9%, Impurity A: 0.01%, Impurity B: not detected,Impurity C: not detected, Impurity D: 0.02%, Impurity E: not detected,Impurity F: 0.02%, Impurity G: 0.02%, Impurity H: not detected, ImpurityI: not detected.

Example 10 Preparation of 2-amino-2-(4-octylphenethyl)propane-1,3-diol(Fingolimod Freebase)

2-nitro-2-(4-octylphenethyl)propane-1,3-diol (3 g) and methanol (60 mL)are charged into a hydrogenation vessel at 25-30° C. and stirred. 10%Pd/C (0.6 g) is charged into the vessel, a hydrogen pressure of 4-5Kg/cm² applied and the reaction mixture is maintained under the sameconditions for about 5 hours. The reaction mixture is filtered through ahyflow bed and washed with methanol (10 mL). The obtained filtrate isconcentrated under reduced pressure at a temperature below 36° C. toobtain 8 mL of concentrated reaction mass. n-Hexane (50 mL) is added,the reaction mixture is cooled to 0-5° C. and maintained at the sametemperature for about 1 hour. The solid obtained is filtered, washedwith n-hexane (10 mL) and dried under vacuum at 36° C. to give the titlecompound.

Yield: 2.0 g

Purity by HPLC: 99.1%

XRPD pattern: FIG. 1.

Example 11 Preparation of Amorphous Fingolimod Hydrochloride

Fingolimod hydrochloride (0.5 g), povidone K-30 (0.5 g), and water (70mL) are charged into a glass beaker at 28° C. and stirred to form asolution. The solution is filtered, charged to the buchi flask of thefreeze drier, cooled to −45° C., and subjected to freeze drying underreduced pressure at 0.1 Torr vacuum, to afford 0.8 g of the product.PXRD pattern: FIG. 2.

Example 12 Preparation of Amorphous Fingolimod Hydrochloride

Fingolimod hydrochloride (1.5 g), povidone K-30 (1.5 g), and methanol(90 mL) are charged into a round bottom flask at 28° C. and stirred toform a solution. The solution is filtered and the filtrate is evaporatedby spray drying, using a Büchi® MINI Spray Dryer B-290 with Büchi® InertLoop B-295, to afford 1.3 g of the product. PXRD pattern: FIG. 3.

Parameters for the Spray Drier of the Above Experiment:

Aspirator: 70%.

Feed rate: 10%.

N₂ pressure: 6-6.5 Kgf/cm².

Inlet temperature: 70° C.

Example 13 Preparation of Amorphous Fingolimod Hydrochloride

Fingolimod hydrochloride (1.0 g), povidone K-30 (1.0 g) anddemineralized water (125 mL) are charged into a conical flask at 30° C.and stirred to form a solution. The solution is filtered and thefiltrate is evaporated by spray drying, using a Büchi® MINI Spray DryerB-290 with Büchi® Inert Loop B-295, to afford 0.95 g of the product.PXRD pattern: FIG. 4.

Parameters for the Spray Drier of the Above Experiment:

Aspirator: 70%.

Feed rate: 10%.

N₂ pressure: 5.0 Kgf/cm².

Inlet temperature: 110° C.

Example 14 Preparation of 4-Octanoylphenethyl Acetate

Aluminum chloride (32.26 g) and 1,2-dichloroethane (160 mL) are chargedinto a round bottom flask equipped with a guard tube and additionfunnel, stirred for 30 minutes, and cooled to 0° C. A mixture of phenylacetate (19.417 mL) and octanoyl chloride (24.66 mL) in1,2-dichloroethane (120 mL) is added over 20 minutes and stirredovernight at room temperature. The mass is cooled to 0° C. and thereaction is quenched with water (400 mL). The mass is extracted withdichloromethane (3×300 mL) and the combined organic layer is washed withbrine solution (2×500 mL), followed by drying the organic layer withsodium sulphate and concentrating under vacuum to give crude as yellowcolor liquid. The crude is purified by silica gel column using 5% ethylacetate in hexane as the eluent, to give the title compound. Yield: 21.7g.

Example 15 Preparation of 4-Octylphenethyl Acetate

4-Octanoylphenethyl acetate (17.6 g) and trifluoroacetic acid (31 mL)are charged into a 250 mL single neck round bottom flask equipped with aguard tube and stirred for a few minutes. Triethylsilane (25.7 mL) isadded and the mixture is stirred overnight at room temperature. Themixture is poured onto crushed ice and then extracted with ethyl acetate(3×100 mL). The organic layer is washed with sodium bicarbonate (200mL), then with brine solution, dried with sodium sulphate, andconcentrated under vacuum to give crude as brown color liquid. The crudeis purified by silica gel column using hexane as the eluent to give thetitle compound. Yield 10 g

Example 16 Preparation of 2-(4-octylphenyl)ethanol

Sodium methoxide (22.6 g) and methanol (450 mL) are charged into a 1liter single neck round bottom flask equipped with a guard tube andstirred for few minutes to form a clear solution. A mixture of4-octylphenethyl acetate (58 g) and methanol (50 mL) is added and themass is stirred for 3 hours at room temperature. Methanol is evaporatedand the residue is diluted with water (300 mL) and extracted with ethylacetate (2×300 mL). The extracts are combined, dried with sodiumsulphate and concentrated under vacuum to give crude as yellow colorliquid. The crude is purified is by a silica gel column using 30% ethylacetate/hexane as the eluent to yield the title compound. Yield: 56 g.

Example 17 Preparation of 4-octylphenethyl methanesulfonate

2-(4-Octylphenyl)ethanol (53 g) and dichloromethane (500 mL) are chargedinto a 1 liter three-neck round bottom flask equipped with guard tubeand addition funnel. Triethylamine (83.5 g) is added, the mixture isstirred for 30 minutes, then it is cooled to 0° C. Methanesulphonylchloride (35.2 mL) is added drop-wise at 0° C. and the mass is stirredfor 3 hours at room temperature. The mass is diluted with water (700 mL)and the organic layer is separated and the aqueous layer is extractedwith dichloromethane (2×250 mL). The combined organic layers is washedwith saturated sodium bicarbonate (500 mL) and brine solution (500 mL).The organic layer is separated, dried with sodium sulphate, andconcentrated under vacuum to obtain the title compound. Yield: 70 g.

Example 18 Preparation of 1-(2-iodoethyl)-4-octylbenzene

4-Octylphenethylmethane sulfonate (70 g) and dry tetrahydrofuran (500mL) are charged into a 1 liter single-neck round bottom flask, equippedwith a calcium chloride guard tube and shielded with light protectingblack cover. The mixture is stirred for 10 minutes, then sodium iodide(133 g) is added and the mixture is stirred overnight at roomtemperature. The solvent is evaporated under vacuum and the residue isdissolved in water (300 mL) and extracted with ethyl acetate (2×250 mL).Ethyl acetate extracts are combined, washed with aqueous sodiumthiosulphate, dried with sodium sulphate, and concentrated under vacuumto give the title compound. Yield: 70 g.

Example 19 Preparation of diethyl 2-acetamido-2-(4-octylphenethyl)malonate

Cesium carbonate (82.2 g), diethyl 2-acetamidomalonate (77.3 g) anddimethylsulphoxide (300 mL) are charged into a 1 liter single-neck roundbottom flask, equipped with a condenser and nitrogen balloon. Themixture is heated to 60° C. and stirred for 3 hours.1-(2-iodoethyl)-4-octylbenzene (35 g) is added at 60° C. and the mass isstirred overnight at 80° C. The mass is cooled to room temperature,quenched with water (400 mL), and extracted with ethyl acetate (3×250mL). The ethyl acetate extracts are combined, washed with brine solution(500 mL), dried with sodium sulphate, and concentrated under vacuum togive a crude compound as a solid. The crude is purified by a silica gelcolumn using 15% ethyl acetate/hexane as the eluent to give the titlecompound. Yield: 65.8 g.

Example 20 Preparation ofN-(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl) butan-2-yl) acetamide

Sodium borohydride (34.49 g) and dry methanol (450 mL) are charged intoa 1 liter three-neck round bottom flask equipped with a guard tube andtwo condensers, and the mixture is stirred for 20 minutes. Diethyl2-acetamido-2-(4-octylphenethyl) malonate (65.8 g) is diluted with drymethanol (50 mL) and then added drop-wise until half of the solution isadded, and the addition is stopped for 1 hour. Addition is thencompleted drop-wise over 30 minutes and the mass is maintained overnightat room temperature. The solvent is evaporated under vacuum, and themass is diluted with water (300 mL) and extracted with ethyl acetate(3×200 mL). The combined organic layer is dried with sodium sulphate,concentrated under vacuum to give the crude mass. The crude is purifiedby silica gel column using ethyl acetate as the eluent to give the titlecompound. Yield: 23.5 g.

Example 21 Preparation of Fingolimod Hydrochloride

N-(1-Hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl) acetamide(23.5 g) is charged into a 250 mL single-neck round bottom flaskequipped with a condenser and 3N hydrochloric acid (100 mL) is added.The mixture is heated to 100° C. and stirred for 3 hours. The mass iscooled to room temperature and maintained overnight. The mass isextracted with ethyl acetate (3×100 mL) and the ethyl acetate extractsare combined, dried with sodium sulphate, and concentrated under vacuumto produce a gummy solid. Ethanolic hydrochloride solution is added tothe solid, stirred for 3 hours at room temperature and the obtainedsolid is separated by filtration and suction dried. The solid isrecrystallized from an isopropyl alcohol solution to give fingolimodhydrochloride. Yield: 5.7 g.

Example 22 Preparation of 3-nitro-1-(4-octylphenyl)propan-1-one

3-Chloro-1-(4-octylphenyl)propan-1-one (110 g) and acetone (1 L) arecharged into a round bottom flask equipped with a condenser and guardtube and stirred. Sodium nitrite (271 g) is added and the mixture isslowly heated to 80° C. and maintained at that temperature for about 21hours. The mass is cooled to 58° C., sodium nitrite (10 g) is added, andthe mass is maintained at 78° C. for about 6 hours. The solvent isevaporated under reduced pressure. The compound obtained is diluted withwater (250 mL) and extracted with ethyl acetate (2×500 mL). The combinedorganic layer is dried over anhydrous sodium sulphate (50 g) andconcentrated under reduced pressure to give solid. Hexane (500 mL) isadded and the mixture is cooled to −10° C. and stirred for 20 minutes.The formed solid is separated by filtration and washed with cold hexane(2×100 mL) to obtain the title compound as an off-white solid. Yield: 75g.

Example 23 Preparation of 3-nitro-1-(4-octylphenyl)propan-1-ol

3-Nitro-1-(4-octylphenyl)propan-1-one (75 g) and methanol (750 mL) arecharged into a round bottom flask equipped with a condenser and guardtube, stirred to 10 minutes and the mixture is cooled to 6° C. Sodiumborohydride (20.2 g) is added in portions over 30 minutes. Allowed themixture to room temperature, stirred for 3 hours and solvent is removedunder reduced pressure to obtain a solid. The solid is diluted withwater (1000 mL), ethyl acetate (1000 mL) is added, the separated solidis filtered. The solid, ethyl acetate (200 mL), and water (200 mL) arecharged in a round bottom flask and stirred at room temperature, and 6NHCl (100 mL) is added drop-wise. The organic layer is separated, washedwith water (200 mL), dried over sodium sulphate, and concentrated underreduced pressure to give the title compound as a yellow liquid. Yield:30 g.

Example 24 Preparation of 1-(3-nitropropyl)-4-octylbenzene

3-Nitro-1-(4-octylphenyl)propan-1-ol (30 g) and trifluoroacetic acid (47mL) are charged into a round bottom flask equipped with a calciumchloride guard tube. The mixture is cooled to 0° C., triethylsilane(32.5 mL) is added, and the mixture is stirred overnight at roomtemperature. The mass is poured onto crushed ice (200 g) and the mixtureis extracted with ethyl acetate (2×200 mL). The combined organic layeris dried over sodium sulphate and concentrated under reduced pressure,to give the crude as a color liquid. The crude obtained is purified bysilica gel column chromatography (100-200 mesh, 500 g) using 5% ethylacetate in hexane as the eluent, and the eluted fraction containing thedesired compound are pooled, evaporated under reduced pressure to givethe title compound. Yield: 19.8 g.

Example 25 Preparation of 2-nitro-2-(4-octylphenethyl)propane-1,3-diol

1-(3-nitropropyl)-4-octylbenzene (43 g) and absolute ethanol (400 mL)are charged into a round bottom flask equipped with a condenser andcalcium guard tube. Paraformaldehyde (43 g) and triethylamine (64.8 mL)are added. The mixture is heated to 70° C., stirred for 3 hours, and isconcentrated under reduced pressure at 50° C. to obtain a solid. Thesolid is dissolved in ethyl acetate (300 mL), the solution is washedwith cold water (2×200 mL), and the organic layer is dried overanhydrous sodium sulphate. The organic layer is concentrated underreduced pressure to obtain a yellow solid. Hexane (500 mL) is added andthe mixture is cooled to −20° C. and stirred for 20 minutes. The formedsolid is separated by filtration and washed with cold hexane (2×100 mL)to obtain the title compound as an off-white solid. Yield: 26 g.

Example 26 Preparation of 2-amino-2-(4-octylphenethyl)propane-1,3-diol

2-Nitro-2-(4-octylphenethyl)propane-1,3-diol (25 g), absolute ethanol(250 mL) and 10% Pd on carbon (5 g, 50% wet) are charged into a 500 mLsteel hydrogenation flask under a N₂ atmosphere and the flask isequipped with a para shaker hydrogen operator. The mixture ishydrogenated with a H₂ pressure of 60 psi (415 kPa) at room temperaturefor 2 hours and filtered through a Celite bed and washed withethylacetate (200 mL). The filtrate is concentrated under reducedpressure at 50° C. to give the title compound as a white solid. Yield:16 g.

The invention claimed is:
 1. A process for the preparation of fingolimodof formula (Ia)

or its salt comprising: a) reducing3-nitro-1-(4-octylphenyl)propan-1-one of formula (VI):

 using a Lewis acid and a trialkyl silane to obtain a compound offormula (VII); and

 b) reacting the compound of formula (VII):

 with paraformaldehyde to obtain a compound of formula (VIII); and

 c) reacting the compound of formula (VIII) with a reducing agent toobtain fingolimod of formula (1a):

 or its salt.
 2. The process of claim 1, wherein the salt of formula(Ia) is a hydrochloride salt.
 3. The process of claim 1, wherein theLewis acid used in step a) is selected from TiCl₄, AlCl₃, or BF₃.
 4. Theprocess of claim 1, wherein the trialkylsilanes used in step a) areselected from triethylsilane, trimethylsilane, or triisopropyl silane.5. The process of claim 1, wherein step a) is carried out in thepresence of a halogenated hydrocarbon solvent, a hydrocarbon solvent orfrom mixtures thereof.
 6. The process of claim 1, wherein step b) iscarried out in the presence of a base selected from an organic base suchas diethylamine, triethylamine, n-butylamine, propylamine,diisopropylethylamine, dicyclohexylamine or an inorganic base such assodium carbonate, potassium carbonate.
 7. The process of claim 1,wherein step b) is carried out in the presence of an alcohol such asmethanol, ethanol, polar aprotic solvents such as dimethylformamide,dimethyl sulfoxide, tetrahydrofuran, acetone, acetonitrile, and aromaticsolvents such as toluene, xylene or mixtures thereof.
 8. The process ofclaim 1, wherein the reducing agent used in step a) is selected fromsodium borohydride, lithium borohydride, lithium aluminium hydride, Pdon carbon, Raney® nickel, or Pd(OH)₂, under a hydrogen atmosphere. 9.The process of claim 1, wherein step c) is carried out in the presenceof an alcohol selected from methanol, ethanol, a polar aprotic solventselected from dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,acetone, acetonitrile, or an aromatic solvent selected from toluene,xylene, or mixtures thereof.
 10. A process for the preparation offingolimod of formula (Ia)

or its salt comprising: a. reacting the compound of formula (VII):

 with paraformaldehyde to obtain a compound of formula (VIII); and

 b. reacting the compound of formula (VIII) with a reducing agent toobtain fingolimod of formula (I a):

 or its salt.
 11. The process of claim 10, wherein the base used in stepa) is selected from an organic base such as diethylamine, triethylamine,n-butylamine, propylamine, diisopropylethylamine, dicyclohexyiamine oran inorganic base such as sodium carbonate, potassium carbonate.
 12. Theprocess of claim 10, wherein the reducing agent of step b) is selectedfrom sodium borohydride, lithium borohydride, lithium aluminium hydride,Pd on carbon, Raney® nickel, or Pd(OH)₂, under a hydrogen atmosphere.13. The process of claim 1, further comprises the purification offingolimod hydrochloride, wherein the purification comprises: a.providing a solution of fingolimod hydrochloride in methanol or methanoland ethyl acetate mixture; b. optionally adding ethyl acetate; c.cooling the solution to a temperature below 10° C.; d. isolatingfingofimod hydrochloride.
 14. The process of claim 13, wherein theisolated fingolimod hydrochloride is crystalline.